Our general objectives are to determine the sites and mechanisms by which antipsychotic drugs produce their biochemical effects and to correlate these biochemical actions with their pharmacological and clinical effects. Specifically we plan (a) to isolate and characterize the binding sites for antipsychotics, (b) to determine whether there are endogenous catecholamines, peptides or other materials that bind to these sites, and (c) to determine the consequences of the interaction of antipsychotics with their binding sites by measuring the effects of acute and chronic treatment with antipsychotics on the concentration of cyclic nucleotides in selected brain areas. Previously we showed that several different chemical classes of antipsychotic drugs block the action of calmodulin, an endogenous calcium-binding protein, by selectively binding to it. In the present studies we will determine whether antipsychotics also bind to calmodulin in vivo, and whether they bind with the same stereospecificity and in same concentrations as those required to produce their pharmacological effects. By binding phenothiazine antipsychotics irreversibly to calmodulin, we also hope to localize calmodulin anatomically and to determine its turnover. Since calmodulin activates specific forms of adenylate cyclase and phosphodiesterase, the interaction of antipsychotics with calmodulin may explain, by a common mechanism, how these drugs interfere with both the synthesis and hydrolysis of cyclic nucleotides. In fact, the evidence that several biochemical actions of antipsychotics can be explained by their binding to, and inhibition of, calmodulin suggests that calmodulin may function as an endogenous receptor for antipsychotics. This raises the possibility that other endogenous materials exist that bind to calmodulin and, thereby, might function as endogenous psychotogenic or antipsychotic compounds. These studies may provide further insight into the biochemical defect that exists in schizophrenia and may suggest a basis for designing novel and more selective agents for its treatment.